There is a rapidly growing body of evidence that Mller glia can are a source of retinal progenitors to promote neural regeneration. Many studies have demonstrated that Mller glia can become proliferating progenitor cells in the retinas of different vertebrate species. Most reports have studied Mller glia-derived progenitors in acutely damaged retinas. However, little is known about the mechanisms that stimulate neurogenesis from Mller glia-derived progenitors in undamaged retinas or retinas undergoing slow, progressive degeneration. Furthermore, the regeneration of retinal neurons in warm-blooded vertebrates is limited compared to that seen in cold-blooded vertebrates. Therefore, the identification of the secreted factors and signaling pathways that permit and/or stimulate neural regeneration from Mller glia-derived progenitors is crucially important to developing new therapies to treat degenerative diseases of the human retina. We have obtained compelling novel preliminary data indicating that signaling through the glucocorticoid receptor (GCR) and the mTor-pathway significantly impacts the plasticity of Mller glia and neurogenic potential of Mller glia-derived progenitors. We will investigate how the phenotype and plasticity of the Mller glia are regulated by GCR- and mTor-signaling in normal, damaged and growth factor-treated retinas. We will use a combination of pharmacological and genetic approaches to selectively activate or inhibit GCR- or mTor-pathways in Mller glia. We will compare and contrast how GCR- and mTor-pathways impact the formation of Mller glia-derived progenitors in chick and rodent model systems with different inherent capacities for retinal regeneration. We expect that the completion of the experiments described in this proposal will provide significant new information regarding how GCR and mTor-signaling influences the formation of Mller glia-derived progenitors and regeneration of retinal neurons. Identification and understanding of the mechanisms that enhance the neurogenic potential of Mller glia is required to develop new therapies for sight-threatening diseases, such as glaucoma and macular degeneration that involve the loss of retinal neurons.